@article{295796aa92e54901a82b2d96d5a9d9b9,
title = "VEGF up-regulation by G93A superoxide dismutase and the role of malate-aspartate shuttle inhibition",
abstract = "A gain of interaction of the amyotrophic lateral sclerosis (ALS)-linked G93A-superoxide dismutase-1 (G93A-hSOD1) with cytosolic malate dehydrogenase (cytMDH), a key enzyme in the malate-aspartate shuttle, diverts neurons towards anaerobic metabolism. Changes in vascular endothelial growth factor (VEGF) are reported in ALS and hypoxia. Here we report that expression of G93A-hSOD1 fused with green fluorescent protein in NSC-34 cells enhanced VEGF expression and levels of VEGF and its upstream regulator hypoxia-inducible factor (HIF-1α). G93A-hSOD1 expressing cells were unable to further up-regulated VEGF in response to Co2+ and H2O2. Amino-oxyacetate that inhibits the malate-aspartate shuttle caused a similar increase in VEGF mRNA and impaired response to H2O2 in WT-hSOD1 expressing cells. Interruption of the G93A-hSOD1/cytMDH interaction reduced VEGF expression in G93A-hSOD1 expressing cells and restored their ability to up-regulate VEGF in response to Co2+ and H2O2. These results demonstrate that the ALS-linked G93A hSOD1 mutation impairs VEGF regulation compatible with the inhibition of neuronal malate-aspartate shuttle.",
keywords = "ALS, Amyotrophic Lateral Sclerosis, HIF, Hypoxia, Malate-aspartate shuttle, SOD1, VEGF",
author = "Yael Mali and Nava Zisapel",
note = "Funding Information: The work was supported in part by the ISF Morasha Research Foundation . YM was supported in part by Biron-Cegla and Gimmelfarb Scholarships . Prof. Nava Zisapel is the incumbent of the Michael Gluck Chair for Neuropharmacology and ALS research. We are thankful to Dr Neil Cashman for the generous gift of NSC-34 cells and to Dr David Gozal for the kind donation of pcDNA3.1 plasmids containing wild-type or G93A-mutant hSOD1 cDNA.",
year = "2010",
month = mar,
doi = "10.1016/j.nbd.2009.12.005",
language = "אנגלית",
volume = "37",
pages = "673--681",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "3",
}